FY2001 NINDS Congressional Justification Narrative

Authorizing Legislation: Sections 301 and 457 of the Public Health Service Act, as amended, Reauthorizing Legislation will be submitted.

This document provides justification for the FY 2000 Non-AIDS activities of the National Institute of Neurological Disorders and Stroke. Justification of National Institutes of Health (NIH)-wide FY 2000 AIDS activities can be found in the NIH section entitled Office of AIDS Research (OAR).

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to reduce the burden of neurological disease. The burden of neurological disease is borne by every age group, by every segment of society, by people all over the world. Nervous system disorders can kill, rob us of every human ability, and inflict incalculable pain and suffering.

NINDS combats disease through research on the healthy and diseased brain, the spinal cord, and the nerves of the body. To initiate and carry out research, the Institute relies on the insight and ingenuity of physicians and scientists throughout the United States. NINDS must continually balance research across a broad spectrum of diseases and levels of application. Fundamental inquiry about how the brain works lays the groundwork for future breakthroughs. Translational research brings insights from basic science to bear on clinical problems. Increasingly, as progress in neuroscience breeds opportunity, NINDS must expand efforts to develop novel therapies and prevention strategies, and clinical trials to evaluate them.

A new optimism that neurological disorders can be cured is energizing patient advocates and the research community. What fuels this hope? The pace of discovery in fundamental neuroscience is accelerating. There is a growing understanding of common mechanisms that contribute to many disorders, with the remarkable implication that success in treating one disorder will have impact on many others. In the last decade the first-albeit far from adequate-treatments have become available to reduce the devastation from disorders like stroke, multiple sclerosis, and spinal cord injury. And, an extraordinary range of new therapies is on the horizon-stem cell transplants, precision surgical repair, "rationally designed" drugs, natural growth factors, and neuroprosthetic devices--to name just a few.

With optimism comes increasing responsibility to translate hope into reality for patients and their families. To meet this challenge NINDS initiated an intensive planning process drawing upon the nation's leading scientists and physicians, the public, and Institute staff. The planning effort has coalesced around several cross-cutting themes that reflect growing synergies among areas of fundamental research and across research focused on different diseases. Each of the themes that follow has profound implications for many disorders.

NeurodegenerationCells in the brain and spinal cord die in many disorders. Parkinson's, Huntington's, and Alzheimer's are familiar "chronic neurodegenerative disorders" in which nerve cells slowly die over years or even decades, but there are many others, such as progressive supranuclear palsy, that are less well known. Progressive deterioration of cells also underlies diseases that afflict children, such as spinal muscular atrophy and Friedreich's ataxia and disorders that strike in mid-life, such as amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) and multiple sclerosis. In the wake of sudden cell death, delayed degeneration of nerve cells and supporting cells also contributes to the consequences of stroke, trauma, and infection.

A major goal of NINDS is to attack neurodegeneration through the entire lifespan whatever the initial cause.

NINDS is vigorously pursing a more complete understanding of the agents that damage cells and trigger cell death and better ways to halt neurodegeneration. Areas for special focus include:

a clearer understanding of how brain cells die. Beyond the influence of particular pathological agents, nerve cells follow a "final common path" to degeneration. The death program, called apoptosis or "cell suicide," activates a step-by-step cascade of enzymes that disrupt the integrity of genes and interrupt normal cell metabolism. Each step offers new therapeutic targets regardless of the initial insult.

how protein aggregation damages neurons. Emerging evidence suggests that the formation of abnormal clumps of proteins is a common mechanism in several neurological diseases. Examples include the Lewy bodies of Parkinson's disease, amyloid plaques of Alzheimer's disease, prion protein aggregates in Creutzfeldt-Jakob disease, and similar aggregates in Huntington's and other inherited disorders. Laboratories in industry and academia are working to exploit a simple strategy: stop the aggregation and stop the disease.

how genes and the environment interact to cause neurodegenerative disease. Some gene defects cause disease directly. But, just as importantly, scientists are confronting the complexities of how other genes influence susceptibility and disease progression. Understanding the interplay between genes and the environment is crucial for prevention and treatment of all diseases, but especially so in chronic neurodegenerative disorders which play out over many years.

Special emphasis area: Neurodegeneration.

Within the next generation, neurodegenerative disorders will rival heart disease as the leading cause of disability and death in this country. Because of the public health imperative and the progress of science, the time is appropriate for NINDS to foster a public-private partnership to attack neurodegeneration on all fronts. This effort will include identification of disease genes and heritable risk factors, expanded research into the causes of neurodegeneration, improved animal models and biomarkers, increased efforts in developing new therapies, translational research leading to trials of new therapies, infrastructure support, and basic research into phenomena such as apoptosis, trophic factors, stem cells, plasticity, neurotransmitters, and neural circuits that underlie all aspects of behavior.

Recent scientific advances in neurodegeneration:

A poptosis occurs in many disorders, but one must ask whether blocking cell suicide would in fact help people. Can rescued cells contribute to normal functions? Several studies in animals suggest that blocking destructive enzymes activated during apoptosis may indeed be a good therapeutic strategy. Most recently, mice genetically engineered to succumb to Huntington's disease survive much longer when apoptosis is blocked. Rodents also recover better after experimental stroke and traumatic injury when apoptosis is blocked by drugs or genetic manipulations, and early experiments suggest the same may be true for ALS. Learning more about apoptosis is essential for developing similar strategies that are suitable for human patients.

Like military strategists who target "command and control" systems, scientists focus on the complex signaling and control pathways within cells. To take just one example, most strokes are caused by ischemia, a severe block of the blood supply to the brain that sets in motion a cascade of harmful processes. Researchers have known for some time that a mild episode of ischemia increases the tolerance of brain cells to a subsequent more serious disruption of blood flow, but this tolerance requires too much time to be useful in protecting against acute stroke. Now scientists have found a chemical signal that is part of the sequence of steps by which brain cells develop tolerance after mild ischemia. This chemical, ceramide, can rapidly induce tolerance in cell culture and animal models of stroke and presents a new strategy to reduce the damage caused by stroke by harnessing the brain's natural ability to develop tolerance for ischemia.

Trophic factors are natural chemical signals that foster the survival and growth of cells in the brain. For decades scientists have studied trophic factors in brain development, but more recently these natural messenger molecules are being applied to sustain adult brain cells. Recently, for example, researchers demonstrated promising results in animal models of ALS. In this terrible disease, the nerve cells that control muscles of the body slowly degenerate. By engineering muscle cells to produce GDNF (Glial Derived Neurotrophic Factor) scientists slowed the progression of ALS in mice. Experiments with GDNF and other trophic factors show promise for treating several other disorders including Alzheimer's and Parkinson's disease, and planning for human trials is underway.

NeurogeneticsGenetics is a powerful unifying force and an avenue for progress in the neurosciences as in all of modern biology. More than half of the genes in the body are important in brain function, and more than 200 genes have already been identified that can contribute to neurological diseases, often providing the first clues to the causes of those disorders. Gene defects cause common disorders like muscular dystrophy, as well as a great many rare diseases that collectively impose enormous burdens on patients and families. For some prevalent diseases, like Alzheimer's, Parkinson's, and ALS, insights from less common inherited forms of a disorder point the way to understanding the more common, non-inherited forms of the disease.

To a modern biologist, genetics is not just about inherited traits or disorders. With today's technology, genetics provides tools to understand at the molecular level how the brain works. From genetic blueprints, neuroscientists can study critical proteins that control the function of the brain: ion channels that control electrical activity, trophic factors that sustain survival and growth of nerve cells, guidance molecules that direct wiring of the developing brain, transporters that ferry essential substances into cells, and receptors that detect signaling molecules. These proteins are already the targets for most drugs that treat nervous system disorders, and new discoveries promise more effective and selective treatments in the future.

One seeming paradox has been a boon to research on the brain. Studying genes teaches us that each person is unique, but also reveals an underlying unity of all life. To an astonishing degree humans share genes with other organisms, even genes critical for brain development and function. By studying similar molecules in simpler organisms like worms, fruit flies, and mice, scientists can dramatically accelerate progress in understanding human health and disease.

A major goal of NINDS is to harness molecular genetics to understand neurological disorders, to define healthy function, and to develop better treatments.

To accomplish this, NINDS will:

gather family data on a worldwide basis to identify new disease genes. The identification of families with inherited diseases is the limiting factor in the discovery of "disease genes." Specific populations in various parts of the world provide unique advantages for identifying these genes.

pursue mechanisms by which disease genes contribute to neurological disorders. Once "disease genes" are identified, the challenge becomes to determine how these mutations give rise to disease.

expand efforts to understand where and when genes are expressed in the nervous system. Location and timing are everything in the brain. The temporal and spatial patterns of gene activity will provide crucial clues about how nerve cells develop, function, react to insult, and respond to treatment.

overcome barriers to effective gene therapy in the nervous system. The potential of gene therapy for treating disorders of the nervous system is great, but the obstacles are also substantial. The nervous system presents unique problems for gene therapy. Among the most critical are bypassing the blood-brain barrier, targeting genes to specific brain regions, and sustaining the expression of introduced genes.

Recent scientific advances in neurogenetics:

One of the most important contributions of genetics is to expedite the creation of animal models of human diseases. Animal models are essential for understanding the underlying biology of nervous system disorders and for testing therapies. Genetic engineering is providing the first useful animal models of many diseases, including ALS, spinal muscular atrophy, Huntington's, Alzheimer's, and several inherited ataxias. Genetically engineered mice and other animals are also providing essential clues for understanding the normal nervous system and its reaction to disease and trauma.

Friedreich's ataxia illustrates the power of genetic technology to bring the bench and bedside closer together. This inherited, progressive disease attacks the nervous system, the heart, and the pancreas. In 1996, an international group of scientists, with NINDS support, discovered the gene that, when defective, causes the disease. The function of frataxin, the protein produced by that gene, was unknown. By examining computer databases, researchers discovered a similar protein in yeast cells. They learned the yeast protein helps regulate iron metabolism, and subsequent data suggested the same might be true for frataxin in humans. Now, a brain imaging technique has shown that iron levels are indeed selectively elevated in the brains of patients with Friedreich's, suggesting that targeting iron metabolism may help treat the disease.

Narcolepsy is a serious brain disorder that affects sleep in a dramatic way. Usually beginning in adolescence, narcolepsy causes extreme daytime sleepiness and sleep paralysis-a frightening inability to move shortly after awakening or shortly after dozing off. For many people the most serious symptom is sudden episodes of muscle weakness called cataplexy, often triggered by strong emotions like anger, joy, surprise, or laughing. After a decade long search, a team of scientists has discovered the gene defect that causes an inherited form of narcolepsy in dogs--Dobermans and Labradors--that closely mimics the disease in people. The gene provides an important clue that may lead to more effective treatment. The gene codes for a receptor, that is the cell's sensor, for a chemical messenger called hypocretin that regulates sleep. People have the same gene and researchers are looking for defective versions in patients with narcolepsy.

Researchers have successfully replaced a missing protein, called delta-sarcoglycan, in hamsters that share the same muscle defect as people with a type of limb girdle muscular dystrophy (LGMD). Scientists engineered the gene for this protein into a virus that had been rendered harmless but retained the capacity to infect muscle cells. Researchers injected the viral particles into the blood supply to a limb and used histamine, a natural regulator, to trick the blood vessels into becoming temporarily leaky enough to allow the viruses to pass through to the muscle cells. This gene therapy procedure efficiently protected muscle fibers from degeneration. The researchers are now adapting their procedure for human clinical trials and similar approaches may be adapted for other disorders.

Channels, Synapses, and CircuitsNerve cells carry out much of their business electrically. Ions, like the positively charged sodium and negatively charged chloride of dissolved table salt, carry the electric current. Ions flow into and out of cells through ion channels, which are tiny pores in cells' membranes that switch open and closed to regulate the flow of ions. Nerve cells communicate with one another at specialized junctions called synapses by exchanging chemical messengers called neurotransmitters that, among other effects, control ion channels. Ensembles of nerve cells, precisely interconnected through synapses, form the circuits that enable us to sense the world, control our bodies, and carry out higher intellectual functions.

Understanding channels, synapses, and circuits offers opportunities for therapeutic breakthroughs in the near future. Most drugs currently used to treat neurological disorders act on these sites. The surprising variety of ion channels and neurotransmitter receptors discovered in the last several years and progress in characterizing their structure at the atomic level are revolutionizing the ways scientists design new drugs.

A major goal of NINDS is to unravel the complexities of information transfer within the brain.

To this end NINDS will:

promote further study of ion channel structure and function. Recent breakthroughs in determining the detailed structure of ion channels in bacteria must be extended to ion channels, neurotransmitter receptors, and transport molecules in more complex organisms. With these structures in hand, scientists can rationally design better drugs for many nervous system disorders.

emphasize the molecular basis of synaptic transmission. Understanding the molecular machinery of synapses will also lead to better therapeutic agents, and is crucial for understanding how the brain works and is affected by disease.

encourage new approaches to circuit analysis. New methods are needed to understand how groups of nerve cells act together in circuits to carry out the critical functions of the brain and spinal cord.

focus attention on particular circuits of immediate medical relevance. Understanding how spinal cord circuits coordinate locomotion is essential for all studies of repair or recovery of function. Other networks of great importance for neurological disorders include the midbrain circuits that regulate sleep and contribute to epilepsy, spinal and higher circuits activated by pain, movement control circuits disrupted by Parkinson's disease and other movement disorders, and cerebral cortical circuits involved in learning, memory, thinking, feeling, and motivation.

Special emphasis area: Ion channels and disease.

Ion channels are the fundamental elements of nerve cell electrical activity, and scientists are discovering an increasing number of diseases that, directly or indirectly, reflect the activity of channels. Drugs targeting ion channels are already a mainstay of treatment for neurological disorders. Recent progress in identifying new channels and in understanding how channels work promise more potent and selective drugs in the future.

Recent advances in channels, synapses, and circuits:

Scientist are beginning to apply new understanding about brain circuits that control movement.

By wiring directly into the brain, researchers have trained rats to control a robot arm just by thinking about it. First, rats were trained in a conventional way to press a lever with their paws to move a robot arm. During this behavior the investigators recorded the activity of several dozen nerve cells through arrays of electrodes implanted in the rats' brains. When the signals from carefully selected nerve cells were amplified, combined appropriately, and sent directly to the robot arm controller, the rats quickly learned to control the arm just by their brains' activity, without using their paws. NINDS has long supported the development of neural prostheses, devices that connect to the nervous system and help restore lost functions like bladder control, hand grasp and hearing. These new results are an important step in moving brain controlled devices from science fiction to reality.

In Parkinson's disease, the brain circuits that control movement become unbalanced when nerve cells die. The nerve cells that initiate movement become dominated by parts of the brain that restrain movement. Surgical treatments for Parkinson's disease attempt to restore the balance. A study of pallidotomy, which removes part of the globus pallidus, suggests that this treatment may be effective when medical therapy has failed, and patients are being followed to see how long the benefits of this treatment last. Another promising approach to restoring movement control in Parkinson's disease is chronic brain stimulation through electrodes implanted deep in the brain's movement control circuits. There is tantalizing evidence that chronic stimulation may not only relieve symptoms but also slow neurodegeneration. Brain stimulation therapies are potentially useful for many nervous system disorders, like epilepsy, chronic pain, depression and even spinal cord injury. In each case understanding the underlying brain circuits, and how they are altered by disease is critical to success.

Breathing disorders during sleep are significant public health problems, particularly "sleep apneas"-the temporary cessation of breathing in adults-and the more severe arrest that may cause sudden infant death syndrome (SIDS). These disorders may reflect unstable activity of the respiratory pacemaker, a group of nerve cells in the brain stem that generates the rhythm of breathing. New methods now enable scientists to directly visualize the activity of respiratory pacemaker cells in living mammalian brain tissue in vitro. Scientists can label pacemaker cells with dye molecules that emit light when the cells become electrically active and use advanced methods to study how electrical activity of identified pacemaker nerve cells controls breathing. NINDS long-term support of methods for visualizing nerve cell activity is providing new tools to study brain cells and circuits.

Cognition and Behavior

For more than a century, neurologists have carefully assessed the changes in personality, memory, language, perception, and cognitive abilities that follow damage to particular areas of the brain. Sometimes deficits are remarkably specific, like an inability to recognize faces of family members or to name certain categories of objects, but damage to other brain areas can cause devastatingly pervasive effects, like inability to form new memories or recognize moral right from wrong. Until the modern era, these behavioral changes could be assigned to particular regions of the brain only at autopsy. Now, not only can brain imaging assess damage in living patients, but functional imaging technologies reveal which parts of the brain are active when normal people engage in carefully designed behavioral tasks. A wide spectrum of experimental techniques to record from and stimulate the brains of animals complement the new imaging methods. Bringing all this new information together to understand how the brain orchestrates higher functions like thinking, feeling, and consciousness, is one of the great challenges of science. The stakes could not be higher: all disorders of the brain involve cognition and feeling in some way.

A major goal of NINDS is to gain a greater understanding of brain mechanisms that underlie higher mental functions and complex behaviors.

seek more precise descriptions of patterns of behavior in developmental disorders. For example, in searching for the mechanisms of autism, it is necessary to better define the behavioral characteristics of the disorder. Equally important is the need to develop powerful non-invasive functional brain imaging methods suitable for the special needs of infants and children.

promote understanding of the neural bases of cognition, emotion, and their interaction. Cognition and emotion affect all neurological disorders, and it is essential to link patterns of brain activity that underlie thought, language, and emotions, and determine how these interactions are altered by disease.

encourage a broad analysis of the experience of pain. To fully understand the experience of pain, an integrated approach is needed, combining anatomical, physiological, and psychological approaches with molecular aspects.

develop better methods for assessing behavior and other neurological functions in the mouse. With the extensive and growing knowledge of mouse genetics, this species has emerged as the best animal model to study the mammalian brain and its diseases. It is therefore essential to better understand mouse behavior, neuroanatomy, and neurophysiology in order to capitalize on this animal's potential.

Special emphasis area: Healthy Brain project.

Neuroscience teaches us that the brain, though shaped by genes, is exquisitely sensitive to experience and the environment throughout life. As we combat disease, NINDS is expanding its view towards promoting a healthy brain throughout life. We should not accept nervous system decline any more than we accept deteriorating cardiovascular health as the inevitable consequence of disease or of normal aging, and we must learn to apply insights about brain development to maximize the cognitive and emotional function for all Americans. The Healthy Brain Project will develop plans for long term studies of cognitive health and risk factors that compromise brain function. These results, like similar studies of the heart, will ultimately lead to recommendations for interventions and life-style changes to improve cognitive and emotional health of the American public.

Recent advances in cognition and behavior:

Neuroscientists have made substantial progress in understanding how the brain distributes different analytical tasks among its parts. For example, separate visual areas of the cerebral cortex compute an objects location, color, shape, and motion. However, scientists are only beginning to wrestle with the "binding problem," that is, how the brain puts the separate processing streams back together into unified perception, movement control and consciousness. One clue seems to be precisely synchronized electrical activity of nerve cells in interacting parts of the brain, especially between a midbrain region called thalamus that generates oscillations and the cerebral cortex with which the thalamus is intimately connected. While we are still far from comprehending the solution to the binding problem there are already glimmers that the explanation may reveal common elements of disorders as varied as depression, chronic pain, and Parkinson's disease.

Treating prolonged, intractable pain is one of the most important and daunting challenges that confronts health care professionals today. Despite recent advances in understanding the mechanisms of pain, millions of people continue to suffer, and we know relatively little about how higher brain centers produce the subjective experience of pain. Until recently, doctors could only rely on what patients communicated to gauge the severity of pain and to understand how the brain processes pain signals. Now, for the first time, scientists using functional brain imaging techniques such as MRI and PET have begun to map the activity of specific brain areas while people actually experience acute and chronic pain. While it may take years to fully unravel the implications of this new information, brain imaging studies are already helping to dispel false notions about pain and, hopefully, will lead to new approaches for treatment and prevention.

Dyslexia is a deficiency in reading ability despite normal intelligence and education. Some researchers argue that impaired ability to discriminate rapid changes in sound, such as the sounds of spoken language, is at the root of the problem. Others suggest that deficits in more complex processing of information must be involved because most dyslexic persons speak and understand spoken language very well. Using a technique called magnetoencephalography, which measures magnetic fields generated by the brain's electrical activity, scientists have now provided direct evidence that the brains of dyslexic persons respond differently than normal readers to brief, rapidly changing sounds. Scientists have already begun to apply insights about the brain and dyslexia to helping children with reading disabilities.

Neural Development, Plasticity, and Repair

The brain is populated by billions of cells, with more varied "personalities" than a modern American city. A newborn nerve cell may migrate from its origin in specialized proliferation zones of the brain through distances equivalent in scale to New York to San Francisco. Once in place, a nerve cell links up precisely with thousands of other nerve cells. Even a small child, whose brain is still rapidly changing, can analyze the world in ways that the best supercomputers cannot match. Understanding how the human brain develops is one of the great mysteries of modern science, one which has profound implications for treatment of nervous system diseases.

Infants and children suffer a wide spectrum of nervous system disorders. Some are the same as those that afflict adults-brain tumors, injury, infection-but may have more pervasive consequences in the developing brain. Others are unique to children. The very young always present special problems for treatment, and perhaps also a special sense of obligation. There is another far reaching implication of our growing understanding about how the brain changes. The last several years have brought an increasing realization that even the adult brain retains an astonishing capacity for change-indeed, that "plasticity" underlies our ability to learn and adapt throughout life. Harnessing the capacity of the nervous system to change, perhaps even reactivating mechanisms that guide early development, offers the best hope for restoring function in the injured or diseased brain.

Combating disorders that affect children and using the remarkable new discoveries about early development to enhance repair and regeneration in the mature nervous system are major goals for NINDS.

Specific areas for focus in the immediate future include:

encouraging the development of stem cell biology to repair the injured nervous system.

elucidating mechanisms of synapse formation and plasticity. New understanding about molecules that guide the growth of nerve fibers, or inhibit their growth, brings hope that damaged nerve fibers may be coaxed to regrow. Encouraging regenerating nerve fibers to form appropriate synapses may be the limiting factor in restoring function.

restoring function in neurologically disabled people. We must utilize new understanding about nervous system development and plasticity to repair the nervous system injured by spinal cord injury and stroke, for example. Stem cells to replace lost cells, neurotrophic factors which stimulate nerve survival and growth, chronic brain stimulation, behavioral techniques, and novel training methods beyond traditional rehabilitation must all be part of the effort. NINDS must also continue its long term programs to develop neural prostheses, electronic and mechanical devices that connect with the nervous system to restore lost function.

Special emphasis area: stem cell biology:

Neural stem cells are immature cells that can multiply and specialize to form the many cell types that make up the nervous system. In no area of medicine is the potential for harnessing stem cells to treat disease greater than for disorders of the nervous system.Stem cells may help treat devastating inherited disorders that affect children like Tay-Sachs disease, diseases such as multiple sclerosis in adults, and neurodegeneration in older people from Parkinson's and Alzheimer's diseases. Perhaps most surprisingly, even the adult brain harbors stem cells that might be recruited to help recover from disease. Although these cells may not have all the capabilities of stem cells from earlier developmental stages-we don't know yet-they respond to a host of internal and environmental factors. Exercise, circulating hormones, learning, and an enriched environment can promote, while stress can diminish, production of new nerve cells in the brain. The key to applying the extraordinary potential of stem cells is to learn the natural signals that control their proliferation and specialization. Enormous scientific and ethical considerations must be addressed, but the potential applications are widespread.

Special emphasis area: spinal cord injury.

Restoring function following spinal cord injury remains a high priority for NINDS because of the burden of spinal cord injuries and the potential for applying advances in basic neuroscience toward this problem. One goal is to obtain a clear vision of the temporal and spatial changes in gene expression following injury. Increased efforts are also needed to understand spinal cord circuits in the normal and injured spinal cord, to explore modulating those circuits by electrical or chemical intervention, and to develop techniques for chronically modulating selected local circuits in the spinal cord. The role of spinal cord plasticity, both as a cause of problems like pain, and as an opportunity to facilitate functional recovery, is another area that is especially important. Finally, NINDS must encourage scientists to exploit the new information about the development of the embryonic spinal cord for spinal cord repair and regeneration.

New evidence suggests that neural stem cells can repair damage from brain disorders not only in disorders where damage is highly localized, like Parkinson's disease and spinal cord injury, but also those in which cell dysfunction is widespread in the brain, as in multiple sclerosis and stroke. Scientists injected cultured neural stem cells into the brains of newborn "shiverer" mice. These mice lack a key protein needed to form myelin, the essential electrical insulation that surrounds nerve fibers. Transplanted stem cells migrated throughout the brain and matured into oligodendrocytes, the cells that normally form myelin. These cells produced enough myelin that tremors almost completely disappeared in some mice. Stem cells may ultimately help people with multiple sclerosis, which also disrupts myelin, and other diseases with widespread effects in the brain.

Brain imaging has revolutionized research on, and treatment of, nervous system disorders. Adapting these advances to the needs of infants and children presents special challenges, but is critically necessary for understanding pervasive developmental problems as autism, traumatic brain injury, and neonatal ischemia. To meet the needs, NINDS has undertaken special efforts in developing imaging databases of the very young brain and in fostering appropriate technologies. Near Infrared Spectroscopy (NIRS) is one such technology that offers special promise for infants and children. The relative transparency of biological tissues, especially the skull of very young children, to near-infrared light allows non-invasive measurement of critical brain functions, like oxygen levels and blood flow. This technology offers the prospect for mobile, bedside imaging without large, expensive, noisy, confining (and scary) equipment, and may be adaptable for inexpensive, continuous bedside monitoring of adults.

Neural EnvironmentLike crew members on a movie set who outnumber the actors, glial cells far outnumber nerve cells in the brain. "Glia" comes from the Greek for glue, but glial cells do much more than hold the brain together. They regulate the brains fluid environment, divide metabolic duties with nerve cells, react to infection and injury, guide migrating nerve cells during development, ensheathe nerve fibers with critical electrical insulation, and interact with nerve cells through chemical signals in complex and poorly understood ways. In addition to glial cells, other non-nerve cells, such as immune cells play critical roles in controlling the internal environment of the brain during health and diseases.

Neurological disorders may arise when glial and other supporting cells are compromised, as in multiple sclerosis, or non-neural cells may themselves become aggressors, as in most brain tumors and in autoimmune disorders. Immune cells react to infections and trauma, and even participate in chronic neurodegenerative disorders. A major goal of NINDS is to exploit new methods for studying how non-neuronal cells maintain the delicately balanced environment of the nervous system. To facilitate research in this area NINDS will:

encourage research on the functions of glia and other non-neuronal cells. Non-neuronal cells play critical roles in perinatal injury, multiple sclerosis, tumors, infections, and in the reaction of the brain and spinal cord to injury and stroke. In addition to their traditional roles in maintaining the brain's milieu, possible new roles of glia in information processing demand investigation.

intensify efforts to understand the blood-brain barrier. Glial cells, together with the endothelial cells that line blood vessels in the brain, make up the blood-brain barrier that restricts the entry of potentially harmful substances from the general circulation, but also limits access of potentially therapeutic compounds, like natural growth and survival factors.

expand ongoing molecular analysis of brain tumors. Glial cells are responsible for the most aggressive type of brain tumor, the glioblastoma. A goal is to determine which genes are activated when this tumor arises, as a path toward understanding what causes the uncontrolled tumor cell proliferation and the destructive invasion of surrounding brain tissue.

Special emphasis area: brain tumors.

Decades of research have taught us that all forms of cancer are in a real sense genetic disorders. While most tumors are not inherited, all reflect mutations or improper activation of genes that control the behavior of cells. For this reason, NINDS, in collaboration with the NCI Cancer Genome Anatomy Project (CGAP), has embarked on an ambitious Brain Tumor Genome Anatomy Project (BTGAP). BTGAP is developing a comprehensive molecular profile of primary brain tumors at progressive levels of malignancy. Already, well over 1000 unique genes have been detected, and the number is still climbing, which makes BTGAP not only a productive source of new information about brain tumors but also one of the richest of all sources for revealing human genes. BTGAP is providing this new information--including cDNA libraries, clones, and sequence data--to all scientists through the CGAP database infrastructure. Understanding brain tumors at the molecular level is the key to developing effective therapies.

Recent scientific advances in non-neuronal cells:

Citizens of New York City need not be reminded of the public health consequences of nervous system infections. In keeping with NINDS' long history of research on nervous system infections, an Institute supported investigator was critical in identifying the West Nile virus responsible for the encephalitis cases in New York. Decades of research on the once obscure agent responsible for Creutzfeldt-Jakob disease and "mad cow disease" have also proven essential in confronting the public health issues surrounding this problem. An unexpected dividend is possible insights into the mechanisms of neurodegenerative disease like Alzheimer's.

The Institute is continuing its broad program of research in infectious agents, including possible links of the body's reaction to infection in causing such common disorders as multiple sclerosis.

A lack of oxygen during birth was long blamed for cerebral palsy. However, while compromise of the oxygen supply has become much less common, the rate of cerebral palsy has not declined. New findings show that blood from newborns later diagnosed with cerebral palsy contains higher than normal concentrations of cytokines and interferons, chemical signals by which active immune cells communicate. Newborns who later exhibited cerebral palsy also had indicators of blood clotting abnormalities that predispose older children to strokes. Thus, the immune system, whether reacting to infection before birth or by autoimmune reactions, may play a previously unrecognized role in causing cerebral palsy. This knew knowledge may open new approaches to preventing cerebral palsy.

The blood-brain barrier normally protects sensitive nerve cells of the brain and spinal cord by restricting access of potentially harmful substances from the general circulation. However, the barrier also prevents access of many drugs than might be useful in treating disorders of the brain and spinal cord. Neurosurgeons have now developed a method of targeting drugs where they are needed through small tubes in the brain and spinal cord. The method relies on carefully controlled convection, that is, bulk flow of fluid, within the spaces between cells. This approach has already been successfully used for administering anti-cancer drugs to brain tumors in patients and for delivering drugs in an animal model of Parkinson's disease, and it opens many new opportunities for targeting drugs where they are needed in a wide range of diseases of the brain and spinal cord.

Experimental Therapeutics and Clinical TrialsTraditionally medicine has been able to do little to halt or reverse most neurological disorders. That is changing. The last decade has produced the first emergency treatments that reduce disability following stroke and spinal cord injury, the first treatments that slow progression of multiple sclerosis, significant inroads in preventing stroke, new treatments for epilepsy, practical neuroprosthetic devices to improve the independence following spinal cord injury, and new approaches for treating Parkinson's disease. Until recently most scientists felt it irresponsible to speak too hopefully about progress against brain diseases, but now, with rapid progress in neuroscience, optimism is becoming the norm.

Ongoing clinical trials include studies of surgery, deep brain stimulation, traditional and novel drugs, diet, and immune therapies for Huntington's, Parkinson's, epilepsy, traumatic brain injury, stroke and several other disorders. To insure the pipeline of treatments for clinical testing continues to flow, NINDS must support fundamental neuroscience research in areas like stem cell biology, trophic factors and circuits; promote research into the mechanisms of disease; provide better animal models for human disorders; develop biomarkers to more efficiently evaluate the effectiveness of treatments; develop means to deliver drugs to specific targets in the nervous system; and explore innovative methods for developing new therapies, such as combinatorial chemistry and structure-based rational drug design. By the time a neurodegenerative disorder like Parkinson's is diagnosed, more than 80% of the nerve cells in critical regions of the brain may already be gone. So, finding better ways to identify disease early in its course is especially urgent as therapies become available that might slow neurodegeneration.

The great challenge for NINDS is to quickly translate the remarkable progress of modern neuroscience into useful therapies. A major goal of NINDS is to enhance our program in clinical research and epidemiology to develop more effective therapies and prevention strategies. To this end the Institute has extensively reorganized its extramural programs and will use every funding mechanism available, including new pilot and planning grants for clinical trials. Given the rapid-and sometimes quite surprising-scientific advances and technological breakthroughs, the NINDS must be also vigilant about exploring the ethical dimensions of new research avenues.

Scientific advances in experimental therapeutics and clinical trials:

NINDS is continuing its long-term efforts to prevent stroke which have had a major impact on public health. A series of clinical trials over more than a decade has progressively refined our understanding of who is likely to benefit from surgery, such as carotid endarterectomy, and drugs, such as aspirin and warfarin. Most recently, a trial has shown that low doses of aspirin given at the time of surgery work better than higher doses. Among the ongoing trials are investigations of a surgical treatment, called stenting, for people with narrowing of the arteries that supply blood to the brain, a study of vitamins for preventing stroke in people with certain risk factors, examination of the relationship between estrogen and stroke, evaluation of heparin in patients with acute of progressive stroke, continuing studies of the drugs warfarin and aspirin, and a community based study of the drugs ticlopidine and aspirin to prevent stroke in African-Americans, who have a higher rate and more severe strokes than white Americans.

A brain or cerebral aneurysm is a weak spot in the wall of a cerebral artery that balloons out due to pressure from the blood. When a brain aneurysm ruptures, it causes a hemorrhagic (bleeding) stroke. Surgery can repair aneurysms, but brain surgery carries its own risks, including stroke or infection that can impair mental ability, damage the brain, or even cause death. The lack of information about the risks of unruptured intracranial aneurysms and about the risks of surgery has hampered physicians and patients in deciding whether surgical treatment is warranted in a particular case. A new study examined in detail how the size and location of an unruptured aneurysm and a patient's medical history influence the likelihood that an aneurysm will burst. The study also followed the frequency and severity of problems following surgery for an unruptured aneurysm. With this information in hand, patients and their physicians can make a better informed choice about treatment.

Duchenne muscular dystrophy (DMD) is a progressive degenerative disorder of muscle caused by a mutation in the gene coding for dystrophin, a structural protein of muscle. No treatment is available to halt the degeneration, and patients die of respiratory or cardiac failure by their teens or early twenties. In about 15% of DMD patients, the mutation is a premature stop codon, that is, an incorrect code word in the gene that causes the protein synthesizing machinery of the cell to halt, resulting in the absence of dystrophin. The mdx mouse model of DMD also results from a premature stop codon. Scientists have now demonstrated that the antibiotic gentamicin can partly suppress the premature stop in mdx mice, and thereby restore muscle strength and prevent muscle degeneration, even when the antibiotic is administered in combination with drugs that block its serious side effects.

High blood pressure (hypertension) has many possible causes. Rarely, hypertension results from a benign tumor of the adrenal gland that releases potent chemicals such as adrenaline into the bloodstream. Although rare, these tumors, called pheochromocytomas ("pheos") are important in clinical medicine. Surgical removal of a pheo can cure the hypertension, but an untreated pheo, in response to seemingly mild stress, can secrete chemicals that produce catastrophic consequences such as heart attack and sudden death. Findings such as episodic severe hypertension, sweating, pallor, or headache may suggest to a physician that a pheo is present, but blood tests are not sensitive enough to detect pheos in all patients. Researchers have now developed an effective blood test to detect pheos. This should increase the efficiency and decrease the cost of diagnostic evaluation of patients with high blood pressure and findings that suggest a pheo.

Infrastructure

To NINDS "infrastructure" means bringing the right people together with the appropriate tools to attack diseases. Scientific discoveries and new technologies are changing the way research is carried out. All NINDS planning panels emphasized the need to lay the foundation for neuroscience in the coming years through support for infrastructure, shared resources, and collaborative consortia. The eleven new Morris K. Udall Parkinson's Disease Centers of Excellence represent one approach to bringing scientists from many disciplines together to attack a common problem, and the Institute is exploring other mechanisms to promote cooperation where it is critically needed. Last year NINDS began a program of small equipment supplements. The response indicated a huge unmet need for maintaining the effectiveness of day-to-day operations, and this program will continue, along with support for larger shared facilities, to insure that research is not handicapped by the lack of tools. NINDS must also train a new generation of scientists. Drawing from the nation's full diversity of talent is especially critical for addressing unacceptable health disparities, and the Institute is expanding its pioneering efforts in this area. To build the foundation for the neuroscience enterprise of the future, NINDS will:

Commit a portion of new funds to shared resources. Some high priorities include:-access to emerging array technologies that allow scientists to monitor the activity of thousands of genes during health, disease, and treatment.-access to and continued development of brain imaging, for monitoring brain structure, activity, and biochemistry in adults and experimental animals, and methods adapted for the special needs of infants and young children;-computational neuroscience and bioinformatics;-access and creation of critical genetic resources including genetically modified animals

Utilize new funding mechanisms. Including core grants, small awards to foster collaborations, and regional facilities.

Develop new training initiatives.

Address health disparities. NINDS has created a new Office of Special Programs in Neuroscience to focus on training a diverse cadre of scientists and physicians and to focus efforts on health disparities in neurological disorders, such as stroke.

Special emphasis area: Health Disparities.

NINDS has developed and implemented a long term strategy to reduce the disparities among populations for diseases and disorders of the brain, spinal cord and peripheral nervous system. Minority populations are typically at greater risk for stroke, neurological complications of AIDS and diabetes, and traumatic brain and spinal cord injury. In collaboration with the NHLBI and NCRR, the NINDS is cooperatively engaging minority medical schools in developing sustainable, replicable and culturally appropriate prevention and intervention research programs on stroke and HIV/AIDS. NINDS will empower these programs by assisting the grantees in developing effective collaborations with research intensive institutions and community-based organizations.

An Integrated Neuroscience Community at NIH

The NIH intramural environment provides unique opportunities for interdisciplinary collaborations, for long-term studies, and for rapid response to problems of special urgency. A recent example is the creation of an emergency stroke program, in cooperation with local Suburban Hospital. Now that NINDS sponsored trials have demonstrated the efficacy of emergency stroke treatment, this program will focus on developing better emergency diagnoses and treatments. The NIH Clinical Center has always excelled at bringing the research bench closer to the hospital bedside, and the opportunities the Clinical Center provides for patient oriented research are especially critical in today's competitive health care environment. NINDS is working with other NIH Institutes to develop an integrated an neuroscience community which can work closely, as a valuable resource, with the broader neuroscience research community.

Special emphasis area: an integrated neuroscience community at NIH.

The NIH intramural neuroscience program is well on the way to regaining its position of world leadership. Efforts spearheaded by the NINDS and NIMH Scientific Directors have resulted in outstanding recruitments and significant redistribution of resources, and the entire enterprise has prospered under new NIH procedures for recruitment and tenure of independent investigators. The new Neuroscience Center, funding for which is included in the FY 2001 request for Buildings and Facilities, will provide an environment conducive to modern neuroscience research.

Epilepsy-the themes come together

Epilepsy has been part of the human condition for as long as recorded human history. Stone tablets from the ancient Babylonians, papyruses from the Egypt of the pharaohs, and the oldest medical treatises from China and India each describe epileptic seizures with detail that a 20th century neurologist would recognize and appreciate. For most of the last 3000 years epilepsy was ascribed to cosmic forces, demons and ghosts. Persons with epilepsy were shunned and segregated. The stigma of epilepsy has persisted even into modern times, but most people now understand what astute ancient physicians, like Hippocrates, recognized a long time ago. Epilepsy is a disease of the brain.

The epilepsies are chronic brain disorders characterized by spontaneous, recurrent seizures. In the modern era, each fundamental discovery about the workings of the brain has brought new understanding about epilepsy. We now know that seizures reflect "electrical storms" in the brain, during which groups of nerve cells rapidly fire electrical impulses in synchrony. The manifestations of a seizure depend on which parts of the brain are affected. Indeed, with knowledge about which parts of the brain control what behaviors, neurologists can sometimes map storms rolling across the brain by the symptoms exhibited. Seizures range from brief lapses of attention (absence seizures) to limited motor, sensory, or psychological changes (partial seizures) to prolonged losses of consciousness with convulsions (tonic-clonic seizures). The frequency of seizures also varies greatly. Seizures can be so common that they severely incapacitate a person's ability to work, study, or maintain social and family relationships, and can have devastating consequences for development in children. In some cases seizures can progress to a potentially fatal condition of sustained seizures called status epilepticus.

Head injuries, brain tumors, stroke, poisoning, developmental problems, genetic conditions, and infectious illnesses can all cause epilepsy, but in more than half of all cases no cause can be found. Treatments for epilepsy now include drugs, surgery, diet, and electrical stimulation, but far too many people suffer from intractable epilepsy for which no adequate treatment is available. Epilepsy serves as a good illustration of how all the major themes of this document must come to play in confronting every nervous system disease in the coming years.

Ion channels and neurotransmitter receptors mediate the excessive brain electrical activity during seizures, but scientists are only beginning to understand how changes in channels, synapses and circuits underlie epilepsy. Even when seizures can be "controlled" with some combination of drugs, people with epilepsy must endure troublesome side effects. Most drugs for epilepsy work on channels and synapses. In the last several years hundreds of sub-types of ion channels and synaptic proteins have been distinguished, each with different characteristics and distributions in the brain. Drugs rationally designed to target these proteins offer the prospect of more effective seizure control, with fewer untoward effects, in the future.

Genetics has recently come to the fore in the study of epilepsy. Scientists have so far discovered several genes that provoke inherited seizure disorders, but more than 100 different genetic causes are suspected. Not surprisingly, some of these are defects in ion channels and neurotransmitter receptors, but others provide quite unexpected leads for understanding how epilepsy comes about, even in the non-inherited cases. New animal models for understanding epilepsy and testing treatments are one far reaching result of genetic studies.

Beyond the epilepsies that are caused by mutations in a single gene, there are many more epilepsies that are caused by a combination of several genes acting together. This degree of complexity presents perhaps the greatest challenge for the genetics of epilepsy. As for many other common disorders we must understand how many genes interact with one another and with environmental influences to influence the susceptibility to epilepsy and its progression. NINDS recently hosted a workshop with key scientists and representatives of patient groups to help catalyze the exploration of epilepsy genes and complex interactions among genes that influence epilepsy.

With better understanding about how the normal brain develops, there is a new appreciation for how development gone awry can contribute to epilepsy. Developmental neuroscientists are beginning to unravel the secrets of how new nerve cells migrate to their proper locations. Investigations of this process have revealed that gene mutations that disrupt the early migration of nerve cells in the developing cerebral cortex can cause epilepsy. In one extreme case, abnormalities in a gene called doublecortin cause migrating nerve cells to stop short of their target location forming two cerebral cortices, one beneath the other. Other genes cause more subtle defects, with islands of misplaced nerve cells in the brain. Brain imaging reveals that developmental anomalies are far more common than were suspected, and may cause many cases of idiopathic (poorly understood) epilepsy.

Plasticity comes into play during epilepsy in many ways. In a dramatic illustration of the brain's capacity to adapt, young children with very severe epilepsy who must endure the removal of an entire half of their cerebral cortex show an astonishing capacity to recover function. The remaining half of the brain takes over many functions of the lost half. Encouraging adaptive plasticity is crucial for many disorders, but plasticity can also have a bad side. Scientists trying to understand how epilepsy develops have for many years studied a process called kindling. In kindling repeated excitation of a brain circuit strengthens certain synapses predisposing the brain to seizures in the future. The synaptic changes during kindling are similar to synaptic plasticity that scientists are exploring as the basis of normal learning and memory. In another expression of plasticity, nerve fibers called "mossy fibers" in a brain region critical for epilepsy exuberantly sprout new branches in persons with epilepsy. Understanding how brain plasticity may both promote epilepsy and help the brain adapt when challenged by this disease is critical for the future.

Neurodegeneration, the neural environment, and cognition and behavior also are important considerations in epilepsy. Epilepsy is not generally thought of as a neurodegenerative disorder, but brain cells die in this disease, and death of brain cells from stroke, infection or trauma can provoke epilepsy. Mechanisms like "excitotoxicity" that contribute to neurodegeneration in other disorders probably come into play. Understanding how neurodegeneration contributes to and results from the progression of epilepsy is an important concern. The neural environment is also a crucial consideration in epilepsy. The blood-brain barrier limits access of potentially therapeutic drugs. Glia play a critical role in clearing excitatory neurotransmitters and limiting overexcitation. The reactions of glia and of immune cells may also contribute to epilepsy that follows infection and trauma. The effects of epilepsy on cognition and behavior are a concern in many respects, especially in children. To take one example, surgery to remove the brain "focus" that initiates seizures is the best treatment for some types of epilepsy. In preparation, surgeons must carefully identify and protect "eloquent" areas of the brain that serve essential functions like language. New functional imaging methods used to study how the brain controls cognition and behavior are being intensively explored to help this process.

NINDS has a long history of efforts in experimental therapeutics and clinical trials for epilepsy. Thirty years ago the Institute began a program for standardized screening of potential anti-epileptic drugs from academia and companies worldwide, along with an expanded program of evaluating drugs in clinical trials. Therapeutic approaches for epilepsy now include drugs, surgery, electrical stimulation, and diet, all of which continue to be targets of NINDS interests. As we enter an era when therapies for neurological diseases are becoming more commonplace, NINDS' experience with epilepsy will help guide efforts directed toward other diseases and other technologies, such as high throughput screening methods for drug discovery.

Finally, epilepsy can affect people of either sex at any age, but, like every neurological disease, each patient confronts special problems. In the very young, the potential consequences of the disorder itself, and of the drugs used to treat it, on brain development are special concerns. Febrile seizures, which occur in infants, are also a critical issue. New approaches using animal models and genetics may help resolve the uncertainties that confront parents of infants who exhibit such seizures. Women, especially those of childbearing age, also face special challenges. Many women with epilepsy experience increased seizure frequency during phases of the menstrual cycle in which estrogen is elevated. As with any disease, individual concerns like these can be critical for people coping with the disorder. Scientists are now attempting to understand the effects of epilepsy on development and of hormonal effects on seizures in both human clinical and animal studies.

This spring NINDS is sponsoring a major conference "Curing Epilepsy: Focus on the Future" which recognizes the breadth of science that has implications for this disorder. Even a cursory overview of epilepsy brings home the salience of many cross-cutting themes of modern neuroscience for this disease. Indeed the same could be said for any neurological disease. Each of the hundreds of neurological disorders challenges patients and physicians in a different way, and in no area of medicine it more clear that individual patients, not generic disease labels, must be the focus of treatment. Paradoxically, however, the emerging understanding of the unifying factors among disorders of the nervous system gives the best hope for the future.

Budget PolicyThe Fiscal Year 2001 budget request for the NINDS is $1,050,412,000, excluding AIDS, an increase of $54,327,000 and 5.5 percent over the FY 2000 level. Included in this total is $20,750,000 for the following NIH Areas of Special Emphasis: Biology of Brain Disorders ($7,400,000), New Approaches to Pathogenesis ($2,000,000), New Preventive Strategies Against Disease ($1,900,000), New Avenues for the Development of Therapeutics ($3,200,000), Genetic Medicine ($2,000,000), Bioengineering, Computers, and Advanced Instrumentation ($3,050,000), and Health Disparities ($1,200,000).

A five year history of FTEs and Funding Levels for NINDS are shown in the graphs below:

One of NIH's highest priorities is the funding of medical research through research project grants (RPGs). Support for RPGs allows NIH to sustain the scientific momentum of investigator-initiated research while providing new research opportunities. To control the growth of continuing commitments and support planned new and expanded initiatives, the Fiscal Year 2001 request provides average cost increases of 2 percent over Fiscal Year 2000 for competing RPGs. Noncompeting RPGs will receive increases of 2 percent on average for recurring costs. This strategy will ensure that NIH can maintain a healthy number of new awards, especially for first time researchers.

Promises for advancement in medical research are dependent on a continuing supply of new investigators with new ideas. In the Fiscal Year 2001 request, NINDS will support 606 pre- and postdoctoral trainees in full-time training positions. Stipends will increase by 2.2 percent over Fiscal Year 2000 levels.

The Fiscal Year 2001 request includes funding for 47 research centers, 267 other research grants, including 220 new clinical career awards, and 47 R and D contracts. The mechanism distribution by dollars and percent change are displayed below: